The opioidergic hypothesis suggests an association between genetic variations at the opioid receptor mu 1 (OPRM1) gene locus and opiate addiction. The OPRM1 gene, which encodes for mu opioid receptor, contains several single nucleotide polymorphisms (SNPs) in exon I. Two of these, C17T and A118G, have been reported to be associated with substance abuse. The present study aims to delineate the frequency of these variants in the subjects of Indian origin and study their association with the phenotype of opioid dependence. A118G (rs 1799971) and C17T (rs 1799972) were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. For 118G allele, the control subjects (n = 156) showed a frequency of 0.12 while the opioid dependents (n = 126) had a, ~2.5-fold higher frequency of 0.31 (Odds Ratio 3.501; CI_95% 2.212–5.555; p < 0.0001). For C17T polymorphism, the controls (n = 57) showed a frequency of 0.89 for C allele versus 0.83 seen in dependents (n = 123; odds ratio of 0.555; CI_95% 0.264–1.147; p = 0.121). A significant association was observed between the 118G allele and no association was seen with C17T polymorphism and opioid dependence.